Syringe

ABSTRACT

A prefilled syringe for one or two component medicaments is based upon the use of a vial containing a medicament or one component of a medicament, the vial having an open bottom closed by a piston. When a flexible extension of the piston is coupled with a tubular plunger, and an adaptor cap having an internal needle and an external connection for a needle is placed over a cap of the vial, the latter is converted into a prefilled syringe. The piston may have an axial passage closed by a resealable septum, so that a separate diluent stored in a flexible capsule may be introduced into the vial through the piston by a double ended needle mounted on a further cap applied to the capsule, the further cap being coupled within the tubular interior of the plunger so that the double ended needle penetrates the septum in the piston. The capsule is pushed forward onto the double ended needle when its contents are to be expelled into the vial. The capsule and its cap are then removed and discarded. In an alternative arrangement, the cap of the capsule is coupled to the adaptor cap and the diluent introduced into the vial through a closure secured by the cap of the vial, after which the capsule is removed from the plunger and the latter is coupled to the piston. In further embodiments, the capsule is replaced by a shell vial. The open bottom of the vial is formed with a strengthening bead designed not to interfere with handling of the vials by conventional vial sterilizing, filling and capping machinery.

REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of my copending applicationSer. No. 07/437,203 filed Nov. 6, 1989, and now U.S. Pat. No. 5,137,511which is a continuation-in-part of application Ser. No. 07/072,015 filedJul. 8, 1987 and now U.S. Pat. No. 4,886,495.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to prefilled syringes for use in medical orveterinary treatment.

2. Review of the Art

There has been an increasing trend in recent years to the putting up ofpharmaceuticals in dosage forms so as to minimize the preparationrequired to administer a medicament to a patient and to reduce thechances of dosage errors or contamination. One dosage form which hasbeen gaining rapid acceptance is the prefilled disposable syringe.Various difficulties are however associated with the preparation andusage of such syringes, particularly in the case of preparations which,in ready to use condition, have a short shelf life. Numerous forms ofdual compartment syringe structures have been proposed for the shippingof such preparations with components stored in separate compartments foradmixture immediately prior to use. Although certain structures have metwith some degree of acceptance, they are commonly difficult tomanufacture and/or use because of difficulties in filling the syringewith the components, and because they require extensive manipulationimmediately prior to use. Moreover they are frequently substantiallymore bulky than conventional syringes because in many cases theyfrequently comprise components which effectively represent two syringesin tandem.

Problems in the manufacture of prefilled syringes are not confined totwo component systems and even with single component systems the fillingof syringes under factory conditions is difficult to mechanizeeffectively and requires expensive special purpose syringe fillingmachinery. The same applies to related units prefilled with liquidsrequired for injection or infusion during medical procedures.

Another approach where single component systems are involved isexemplified by British Patent Specifications Nos. 1,252,306 and1,444,119, and U.S. Pat. No. 4,445,895, in which a prefilled cartridgehaving a displaceable plug at one end, and a needle penetrable closureat an opposite end, is inserted into the barrel of a syringe fordispensing of its contents. Whilst such cartridges and the equipment forfilling them are known and available, they are only really suitable forpreparations which can be stored in liquid form, and require either aspecial or a modified syringe for their use. The cartridges themselvesrequire special filling apparatus.

In a further arrangement disclosed in U.S. Pat. No. 3,845,763, acartridge or vial is closed at its bottom end by a slidable plug with adownwardly extending stem, which cartridge or vial is inserted bottomend first into a special holder which carries a double ended needle, sothat the stem is penetrated by the needle and the body of the vial isconverted into a plunger which can be depressed to expel the contents ofthe vial through the stem. The projecting stem means that the vialcannot be filled utilizing conventional vial filling machinery.

The high capital expenditure involved in implementing known prefilledsyringe systems has severely limited their adoption to those few caseswhere their advantages outweigh the substantial additional unit costsinvolved as compared to conventional modes of delivery.

SUMMARY OF THE INVENTION

The present invention seeks to provide a system for the distribution ofpreparations required for injection or infusion in liquid dosage formduring medical procedures, which has a wide range of utility both forsingle component liquid preparations or for two component systems ofwhich one component may be a solid, which utilizes a small number ofcomponents all suitable for mass production using material alreadyapproved for usage in such applications, which is simple to assemble andcan be filled utilizing equipment already available to mostpharmaceutical manufacturers, which minimizes the number of "clean room"operations required, and which minimizes certification problems.

The system is based upon and built around a basic component in the formof a `bottomless vial`. Such a bottomless vial has all of thecharacteristics of a conventional pharmaceutical vial, except that theglass base of the vial is replaced by a piston wholly received withinthe vial and designed to form a hermetic seal with its cylindrical sidewall, the seal being maintained both when coupled and when uncoupledfrom a plunger releasably connectable to the piston for moving thelatter axially of the vial. A particularly important characteristic ofsuch a bottomless vial is that it can be conveyed, filled and cappedreliably by conventional vial sterilization, filling and handlingequipment such as is already possessed by most pharmaceuticalmanufacturers. To this end, the bottomless vial must be free of featureswhich would significantly compromise its stability when handled by suchequipment. A flange or bead is required around the base of the vial forvarious reasons, but must result in no more than a slight increase inthe overall diameter of the vial, and must be configured so as to avoidany substantial increase in its tendency to tip when jostled by othersimilar vials, and the centre of gravity of the vial must not bedisplaced so far upwardly as to substantially reduce the stability ofthe vial.

I have found that it is important that the bottom end of such abottomless vial terminates in a somewhat rounded peripheral bead, whichserves several purposes. Firstly, it strengthens the open end of thevial and reduces stress concentrations and the risk of breakage,particularly during insertion of the piston. Secondly, the roundingproduces a slight internal flare which facilitates piston insertion.Thirdly, it provides means for securely engaging a subsequently appliedpiston retainer which prevents possible ejection of the piston duringshipping and storage of the vial due to gas generation or expansionwithin the hermetically sealed vial above the piston.

Whilst the provision of such a bead is thus highly desirable,conventional formation of the bead as an external projection on the bodyhas the disadvantage increasing the diameter of the bottom of the body,thus both increasing the capability of tipping of the vials while beingconveyed, and possibly providing a ramp for such tripping by riding overor under the beads of adjacent vials unless the external configurationof the bead is carefully controlled. At the same time, particularly forsyringes prefilled with a single component liquid pharmaceutical, theremay be a requirement for a syringe capacity which requires the height todiameter ratio of the body to be increased as much as possible, which inturn requires maximum stability of the vial when conveyed free-standing.

The piston must be capable of maintaining a hermetic seal with the wallof the vial, of integrity comparable to that achieved during capping ofa conventional vial, and this seal should be maintained in storage andduring manipulation of a syringe system incorporating the vial, duringwhich the piston may be subject to non-axial forces transmitted to it bya plunger and tending to break the seal.

In the context of the invention, it should be understood that "vial"refers to a particular type of container, having a rather squatcylindrical body whose height compared to the diameter of its base issuch that it may stand stably on its base whilst being conveyed througha vial handling and filling machinery and whilst subsequently sealed andcapped. Its body should also be free of external projections largeenough to interact with other vials or the filling machinery in a mannersuch as to promote tipping. A vial has a neck with a large enoughinternal diameter to permit filling from a vial filling machine: solidfilling materials will normally require a larger neck than liquids.Vials should not be confused with cartridges, which are comparativelylong and slim, and cannot usually be filled utilizing vial fillingmachinery since they are too tall to rest in a stable manner on theirbases. Cartridges also are typically thin-walled and lack a bead orflange, which renders them fragile, and makes it difficult to insert apiston without excessive risk of breakage.

Accordingly the present invention provides a vial formed of rigidtransparent material and consisting of a cylindrical body, said bodyhaving an open bottom end having an external diameter at most onlyslightly greater than that of the remainder of the body, but sufficientrelative to the height and centre of gravity of the vial as a whole tosupport the latter in a stable manner when conveyed standing on its openend through vial filling and capping machinery, injectable materialwithin the body, a comparatively wide neck at the top of the bodythrough which said injectable material is filled into the body, anexternal peripheral flange surrounding the neck, an elastomeric closureapplied to the neck, a cylindrical cap clamped onto the flange of theneck and having an annular inward extending flange at a top endoverlaying the closure to secure the closure to the neck with theclosure presenting a needle penetrable central portion, an impervioussubstantially solid piston of resilient material sealingly receivedwithin said body at its lower end beneath said injectable material andabove said open bottom end, and an extension integral with said piston,projecting downwardly from said piston but wholly within the body, forestablishing a flexible connection to a syringe plunger in a zonebetween the piston and said open end of the body, whereby said vial maybe converted into a syringe for ejection of the injectable material onmovement of the piston towards the neck, by connection of said syringeplunger to said extension and connection of fluid conduit coupling meansto said cylindrical cap.

According to a further feature of the invention, a vial for forming abarrel and a piston of a syringe comprises a cylindrical glass bodyhaving at one end an open neck and a peripheral external flange aroundan outer end of the neck, and a peripheral rounded bead at an openopposite end, and a piston having a cylindrical head within andconcentric with the cylindrical glass body in slidable hermeticallysealing relationship with the inner surface of the body, the pistonbeing located to define a chamber of volume equal to the nominalcapacity of the vial between the piston head and the neck of the vial,the piston having an integral axial flexible extension of lesserdiameter than the head and extending towards but ending just short ofsaid open opposite end of the body, the flexible extension beingconfigured for releasable coupling with a socket at an end of a plunger,and the vial having at least sufficient stability, when standing on theperipheral bead, to pass reliably through conventional vial filling andcapping machinery without tipping over, wherein the bead is formed sothat the bead is at least partially inwardly of an interior surface of aside wall of the glass body, an external extent of the bead beyond theremainder of an external surface of the wall of the body beingsufficiently slight to leave said external wall free of projectionshaving an adverse effect on the stability of the vial.

The differences between such vials and a conventional vial do notprevent them from being filled and capped in conventional vial fillingand capping machinery; indeed, apart from the replacement of the bottomwall of the vial by a piston as specified, it is a conventional vial,and can be handled normally by the machinery during filling with eitherliquid or solid material. The presence of the piston which is relativelymassive, in the lower part of the vial even helps stabilize the latterduring filling. Furthermore, liquid filled vials may be lyophilizedutilizing special stoppers either as known in the art or as describedbelow. Obviously the cubic capacity of such a vial is less than thecapacity of a conventional vial of comparable overall dimensions but formost purposes this is immaterial.

The invention also extends to a method of packaging a pharmaceutical ina pharmaceutical vial formed of rigid transparent material with acylindrical body and a comparatively wide neck at the top of the body,empt;y of pharmaceutical, in an upright position through conventionalvial filling and capping machinery which fills the pharmaceutical intothe body through the neck, applies an elastomeric closure to the neck,and applies a cap overlaying the closure to secure the closure to theneck to produce filled and capped vials, characterized in that to permitsubsequent administration via injection direct from the vial, acylindrical side wall of each uncapped empty vial is formed so as todefine a bottom opening in place of an integral bottom wall of the vial,with a bead adjacent the bottom opening, any external projection of thebead relative to the outer wall of the vial being too small to causesubstantial instability of the vial when conveyed upright adjacent othersimilar vials during filling and capping, a cylindrical substantiallysolid piston of resilient material is slidably lodged prior to fillingof the vial wholly within the cylindrical side wall above said bottomopening so as to form a hermetic seal with the side wall, an internaland axial extension from the piston, of lesser diameter than the pistonand adapted for subsequent coupling to a syringe plunger, is oriented soas to extend downwardly towards the bottom opening,

A vial in accordance with the invention may be converted into a syringeby the addition of a plunger coupled to the piston and an outer capwhich acts as a needle carrier. More specifically, the syringe includesas well as the vial a syringe plunger connected to the flexibleextension from the piston, and an outer cap engaged over the cap of thevial, the outer cap having a hollow needle projecting axially within thecap and a coupling for engagement with injection means and communicatingwith said hollow needle, the outer cap being axially movable relative tosaid cap of the vial from a position in which the needle ends short ofthe cap of the vial to a position in which it penetrates the cap of thevial. The plunger is provided with radially extending flanges forsustaining actuating forces applied to the syringe through a flange gripprovided on the outer cap or on a plunger guide or piston stabilizerring applied to the open end of the vial.

In a syringe for a two component medicament, it is necessary to providefor packaging of the second component and its admixture with the firstcomponent in the vial prior to dispensing. The invention thus furtherextends to a capsule assembly comprising a generally cylindrical sealedcapsule having walls formed of a flexible needle penetrable material ofsuitable properties, a generally cylindrical neck defined by said wallsat one end of the capsule, said neck having axially spaced inner andouter peripheral ridges, and a generally cylindrical cap applied to saidneck so that a detent within the cap engages the outer peripheral ridgeon the neck, a hollow cannula being formed integral with and passingthrough said cap so that an inner penetrating end within the cap endsshort of the neck of the capsule and an outer end formed either in theform of a needle or a fluid coupling which extends outwardly of the cap,the cap being displaceable relative to the capsule to a position inwhich the detent rides over the inner ridge and the inner end of theneedle penetrates the neck of the capsule, the cap and capsule being ofa diameter such that they can enter the tubular plunger to a position inwhich the outer end of the cannula, if of needle form penetrates theseptum of the piston when the plunger is engaged with the latter. Analternative arrangement may be used where the outer end of the cannulais a coupling, in which case the latter is connected to the coupling onthe outer cap of the syringe, with the plunger being used as a supportfor the capsule prior to being coupled to the piston.

Thus the injection system comprises a sequence of components of whichvarious sub-sequences can be combined to form injection systems forpreparations requiring shipping and storage as two separate components,certain sub-sequences themselves having utility respectively asinjection systems for single component liquid preparations. "Injection"is utilized broadly to cover hypodermic, intramuscular and intravenousinjection, gravity and mechanical infusion, and injection into othervessels utilized in medical treatment or testing. For the purposes ofdescription, the "front" or "top" end of an injection system will beconsidered the end of the system from which a liquid preparation is soinjected.

The arrangement including the capsule assembly has a number ofadvantages in the manufacture and use of prefilled syringes for twocomponent systems; furthermore, without the third cap and the sealedcapsule containing the second component the remaining componentsprovide, according to a further feature of the invention, advantages inthe manufacture and use of prefilled syringes for single componentsystems. The third cap and sealed capsule provide, according to yet afurther feature of the invention, an advantageous subsystem for variousapplications in which a sealed sterile source of a liquid is requiredfor injection, or dropwise introduction into other containers used inmedical procedures. With prefilled syringes for two components systems,either the capsule or the capsule and the third cap, may be sold, orshipped separately. This enables different diluents or sizes of capsuleto be selected, or a common set of diluent capsules to be utilized withsyringe assemblies containing different first components, thussimplifying inventory control.

As an alternative to the use of capsules, shell vials may be utilized inan advantageous manner.

Further features of the invention will become apparent from thefollowing description of a preferred embodiment thereof with referenceto the accompanying drawings.

SHORT DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective exploded view of the mechanical components of asyringe system including a vial in accordance with the invention;

FIG. 2 is a partially longitudinally sectioned, partially exploded viewof the syringe components showing some further details of theirconstruction;

FIGS. 3, 4 and 5 illustrate preparation of the syringe system to providea syringe ready for use;

FIGS. 6, 7 and 8 illustrate exemplary applications of the syringe;

FIGS. 9 and 10 illustrate an optional feature of a vial in accordancewith the invention;

FIGS. 11 and 12 are elevational and exploded views of an alternativeembodiment of the syringe system;

FIG. 13 shows the separated parts a further embodiment of the syringesystem;

FIG. 14 shows, separated, a diluent capsule and cap for use with thesystem of FIG. 13;

FIG. 15 is a longitudinal cross section through the assembled system ofFIGS. 13 and 14;

FIG. 16 is a fragmentary view of a syringe in accordance with theinvention utilized in conjunction with an I.V. bag;

FIG. 17 is an exploded isometric view of the components of a firstembodiment of the syringe;

FIG. 18 is a vertical section through a vial portion of the syringe,ready for filling;

FIG. 19 is a longitudinal section through an assembled syringe, afterdischarge of its contents;

FIG. 20 is a fragmentary longitudinal section on an enlarged scale of aportion of the syringe shown in FIG. 3, showing a modification of thearrangement shown in that Figure; and

FIG. 21 is an enlarged vertical section through the bead of a secondembodiment of the syringe, also showing adjacent parts of a modifiedpiston retainer and finger grip.

FIGS. 22A through I illustrate one mode of utilizing a shell vial inconjunction with a vial in accordance with the invention to provide asyringe system; and

FIGS. 23A through G illustrate a second mode of utilizing a shell vialin conjunction with a vial in accordance with the invention to provide asyringe system.

DESCRIPTION OF THE PREFERRED EMBODIMENT

Referring to FIGS. 1 and 2, a syringe system for the injection of aliquid preparation stored as two components comprises seven primarymechanical components, apart from the components of the preparation,which latter are shown in FIG. 2 but not FIG. 1. The components of thepreparation typically comprise a first component A which may be in anyphysical state suitable for storage in vial, and a second liquidcomponent B, typically but not necessarily sterile water. The liquidcomponent B is stored in a sealed capsule 14 of flexible material,manufactured using conventional techniques from a material, usuallysynthetic plastic, which is compatible with the contents of the capsule.The first component is stored in a cylindrical vial 6, typically ofglass, and capped by an annular cap 4 which retains a conventionalneedle penetrable sealing member accessible through a central opening inthe cap. By a vial is meant a cylindrical vessel which can assume astable upright position supported by its base, the overall height of thevessel exceeding the external diameter of the rim of its base by afactor sufficiently small that it remains stable when passing throughconventional vial filling and capping equipment utilized to fill and capthe vial. This factor preferably does not exceed 2.5 for the presentembodiment, but can be increased by means discussed further withreference to FIGS. 17-21. A neck at the upper end of the vial 6, whichis capped by the cap 4, has a relatively internal diametercharacteristic of such vessels, usually not less than about 7.5 mm forliquid or 10 mm for solids, so that filling with either liquids orsolids can be readily achieved. The cap 4 is formed by an aluminumsleeve, having a flange retaining a sealing member formed by a softrubber disc or plug 5 over or in the front end opening, and tightlycrimped onto a neck at the front end of the vial so as to seal thelatter. A major difference from conventional vials is that theconventional bottom wall of the vial is replaced by an axially movablepiston 8 wholly within the vial and in sealing contact with the vialwalls. When received within the vial 6, this piston in no way interfereswith the handling of the vial using conventional machinery, and inparticular permits the vial to be stood on its base with its neck (whichforms the front end of the vial when in use) upwards as it passesthrough the filling and capping equipment.

The filled vial 6 may be converted into a prefilled syringe by applyingan outer cap 2 over the cap 4 and positively attaching a cylindricalplunger sleeve 10 to the piston 8. The piston 8, typically formed ofrubber, is moulded with a rearward extension 16 with an external thread18, whilst the interior of the front end of the plunger sleeve 10 isformed with a complementary internal thread 20 so that it may be screwedonto the piston 8. The outer cap 2 fits over the inner cap 4 so that ahollow needle 22 formed within the cap 2 does not reach the penetrablezone of the cap 4. On the front of the cap 2 and in communication withthe hollow needle 2 is a coupling adapter 27, for example similar tothose sold under the trade mark LUER-LOK, for connection of the syringeto a needle 28 or other instrumentality (see FIGS. 6-8). To prepare thesyringe for use, the outer cap 2 is pulled back over the inner cap 4 sothat the needle 22 penetrates the cap, and the needle 28 or otherinstrumentality is applied. This should be done without pressing on theplunger sleeve so as to avoid accidental ejection of the contents of thesyringe. The rear ends of both cap 2 and the sleeve 10 are formed withradially extending flanges 24 and 26 respectively which form fingergrips for operation of the syringe. Thus if a user grips the syringe bythe flanges as shown in FIG. 6 and presses them towards each other, thecontents of the syringe can be expelled through the needle 22 and theneedle 28. It will be noted that the rear end of the vial 6 is formedwith only a relatively slight external bead 7 rather than the widefinger flange commonly found on the barrels of conventional syringes. Inthe present arrangement, the flange 24 provides the function of such afinger flange, enabling the bead 7 to be reduced to a size which willavoid such interference between the flanges of adjacent vials as wouldcause tipping when the vials are conveyed in a vertical attitude throughfilling and capping equipment.

In many applications, it is desirable to prevent premature penetrationof the plug 5 by the needle 22, and therefore the cap 2 may be mouldedwith short internal threads (not shown) which prevent rearward movementof the cap 2 unless it is twisted so that the threads bite into the softaluminum of the cap 4 and draw the cap 2 rearwardly so that the needle22 can penetrate the plug.

A prefilled syringe constructed as discussed above has significantadvantages over conventional prefilled syringes in that the vial may befilled using conventional vial filling equipment, and yet may beutilized directly instead of requiring its contents to be transferred toa syringe prior to use as has been conventional in the use of vials.

The vial may also be charged with material which is not directlyinjectable, such as solids which must be dissolved or suspended in aliquid medium prior to injection. In this case the liquid medium issealed as already described in a flexible capsule 14. A third cap 12 iseither applied to the capsule as shown in FIG. 2, or inserted into theplunger sleeve 10 so that a screw thread 30 on the exterior of the capengages the screw thread 20 within the sleeve.

A neck 34 of the capsule 14 has two peripheral ridges 36 and 38. If thecap 12 is applied to the capsule, a detent 40 within the cap is pushedover only the outer ridge 38 so that a rear end portion 42 of a hollowneedle mounted in the cap stops short of the end of the capsule. Byforcing the detent 40 rearwardly over the ridge 36, the needle portion42 can be forced rearwardly so as to penetrate the capsule. A forwardend portion 44 of the hollow needle has a length such that when the cap12 is screwed into the sleeve 10, and the sleeve 10 is screwed onto thepiston 8, the needle portion 44 penetrates a resilient septum 50normally separating axial passages 46 and 48 formed in the front andrear of the piston.

In use, if the capsule 14 and cap 12 are shipped as a separate unit,this unit is screwed into the sleeve 10 (see FIG. 3), and the sleeve 10is pushed into the rear of the vial 6 so that the needle portion 44penetrates the septum 50 of the piston 8 and the thread 20 is screwedonto the thread 18 of the piston (see FIG. 4). This action alsosubstantially unscrews the cap 12 from the thread 20. The capsule 14 isthen pressed forward onto the needle portion 42, and the liquid contentsof the capsule can then be squeezed through the needle and intoadmixture with the first component in front of the piston 8. Thereafterthe capsule 14 and cap 12 may be pulled as a unit from the sleeve 10 anddiscarded (see FIG. 5). The septum 50 reseals as the needle portion 44is withdrawn, leaving a syringe ready for use as illustrated in FIGS.6-8. Alternatively, if the cap 12 is prefitted to the sleeve, the sleeve10 may be screwed onto the piston 8, and the capsule 14 pressed into thesleeve 10 and the cap 12 so as to establish communication between thecapsule and the space forward of the piston, the procedure thereafterbeing the same.

Rather than being used conventionally with a needle as shown in FIG. 6,the prepared syringe may be used for gravitational or mechanicalinfusion as shown in FIGS. 7 and 8. In FIG. 7, the adapter 27 is fittedto a complementary coupling on a gravity infuser 52 to provide a dripfeed, the sleeve 10 having been unscrewed and discarded, together withthe cap 12 and capsule 14, if used. In FIG. 8, the syringe is mounted ina mechanical infuser 54 such as that sold under the trade mark BARD, thelatter being equipped with clamps 56, 58, 60 suited for engagement withthe syringe.

By basing the system on an open-bottomed vial 6 closed at its bottom endby a piston 8 equipped with means such as the screw thread 18 forcoupling it to a plunger of sleeve form, and with a needle penetrableseptum 50, in optional conjunction with sealed flexible capsules ofdiluent, great flexibility in application can be obtained, usingcomponents which are easy to fill, compact to ship, and easy to makeready for use.

Referring now to FIGS. 9 and 10, the rubber disk or plug retained by thecap 4 on the vial 6 may be replaced by a modified plug 60 as shown inperspective from beneath and one side in FIG. 8, and partially installedon a vial 6 in FIG. 9. Use of such a plug 60 is advantageous when thesolid component of a medicament is to be prepared in situ in the vial bylyophilization. The vial is filled with a liquid preparation to belyophilized, and plug 60 inserted to the position shown in FIG. 9, sothat the interior of the vial communicates with its environment througha central passageway 61 and radial bores 62, the passageway and thebores being no larger than needed for the removal of water vapour duringlyophilization. The plug is split at 63 to facilitate moulding. Afterfilling the contents of the vial are rapidly frozen and vacuum dried toleave a solid residue in the vial which can be reconstituted immediatelybefore use. The plug 60 is then moved to the full extent permitted by aflange 64 into the neck of the vial 6 and secured by a cap 4. Whilst aconventional lyophilization stopper could be utilized in place of theplug 60, the latter has the advantage of minimizing the amount of liquidtrapped within the stopper during use of the syringe. For the samereason, the head of the piston 8 is shaped so as to minimize dead spacein the neck of the vial when the contents of the vial are expelledduring use of the syringe.

FIGS. 11 and 12 illustrate an alternate configuration of the syringe.The various components are essentially identical to those alreadydescribed, and the same reference numerals are utilized except that theouter needle 44 of the conduit extending through the cap 12 is replacedby an extension 70 which is configured at its outer end to couple with astandard syringe coupling such as the coupling 27 on the cap 2. Thisenables the capsule 14, once inserted in the plunger 10, to be lockedthrough the extension 70 and the coupling 27 to the cap 2 to produce thecompact assembly shown in FIG. 11. The inner end of the plunger 10 is apress fit on an annular retaining flange 33 formed on the cap 2. Toprepare the syringe for use, the cap 2 is forced rearwardly over the cap4 so that the needle 22 (see FIG. 2) pierces the seal 5, and the capsule14 is forced forward so that it is pierced by the needle 42 and itscontents can be expelled through the needle 42, the extension 70, thecoupling 27 and the needle 22 into the vial 6. The assembly of thecapsule 14 and the plunger 10 can then be released from the remainder ofthe syringe by turning so as to release the extension 70 from thecoupling 27, a needle (not shown) may be applied to the coupling 27, thecapsule 14 is removed from the plunger 11 and discarded, and the plunger11 is screwed onto the coupling 18 to ready the syringe for use. Withthis arrangement, the passage 46 in the piston 8 is not required,although the passage 48 may be retained to save material and enhance theflexibility of the extension 18 of the piston.

A similar arrangement may be utilized for single component medicamentsin which case the capsule 14 and cap 12 are not provided. Thearrangement is advantageous for both single and multiple componentmedicaments since only the vial need be assembled and filled in a cleanroom, the only additional step required over the filling of aconventional vial being the insertion of the piston 8. The plunger 10may be pressed onto the cap 2, and this assembly, if desired togetherwith a needle and/or a capsule 12 and cap 14, may be separatelysterilized and packaged, without endangering the stability or destroyingthe contents of the vial, which will often be sensitive to heat orradiation utilized for sterilization purposes. Since the capsule 12 canwithstand conventional terminal sterilization techniques (see furtherbelow), it can be sterilized independently of the vial. This is a majoradvantage over many two-component syringe systems in which thecomponents are separated only by some form of penetrable plug ordiaphragm and must therefore either be fully assembled in a clean room,or subjected in assembled form to terminal sterilization techniqueswhich may destroy or damage a component of the pharmaceuticalpreparation.

Where the capsule 12 is not being used, it is possible to utilize a cap2 in which the needle 22 is not provided, and instead use a needlearrangement as shown in FIG. 13 or FIG. 15.

Features of presently most preferred embodiments of the invention areshown in FIGS. 13-15. The same reference numerals are used to denote thesame parts in these figures as in the previous embodiments, whereapplicable, and construction and operation are similar except whereotherwise indicated.

FIGS. 13-15 show a further vial and syringe system according to theinvention, the vial comprising a body 6 of rigid transparent material,usually glass although synthetic plastic resins might be utilized incertain applications. The body has the general configuration of aconventional vial except for the absence of a bottom wall. In order tocompensate for the strengthening effect which would be provided by thebottom wall, in order to provide a detent for an optional plungerstabilizer ring 15 described further below, and in order to permit aslight flare at the extreme bottom end of the vial, a rounded bead 7 isprovided around the perimeter of the bottom end of the body, althoughits peripheral extent should not be sufficient to increase substantiallythe diameter of the vial or decrease substantially its stability duringhandling.

A medicament A is retained within the vial by a piston 8. A closure 60substantially fills a neck portion 67 of the vial after the vial, closedat the bottom by the piston, has been filled through its neck portion bya conventional vial filling machine. Although the medicament shown is asolid, it may be a liquid, or filled as a liquid and lyophilized toleave a solid residue. The piston 8 is moulded from rubber, preferablyof at least 50 durometer hardness, and is formed with multiple,preferable three, peripheral ribs 81 on its outer surface, the externaldiameter of the ribs being slightly greater than the internal diameterof the body 6 so that an hermetic seal is established when the piston ispressed into the bottom of the body, initial entry being assisted by theflare mentioned above. The piston is moulded as a substantially solidbody so that it has sufficient rigidity to maintain the desired hermeticseal with the body, any central bores within the piston (see FIG. 15)required to assist needle penetration being of insufficient radialextent to have any significant effect on its rigidity. Although in thepiston shown in FIG. 16, a central bore 48 does just extend into thepiston proper, its axial extent within the piston and its diameter aresufficiently small relative to the piston diameter that the rigidity ofthe piston is not substantially reduced. The longer bore 46 through thepiston shown in FIG. 15 is of even smaller diameter so as not toprejudice piston rigidity.

The piston has a downward extension 18 of reduced diameter, in which thebore 48 is also present. The diameter of the bore 48 forms in this casea greater portion of the diameter of the extension 18, whose flexibilityis thus somewhat increased by its presence. The extension carries on itsouter surface a multistart thread, defined by grooves 16 which terminateabruptly short of the piston, forming abutments serving a purposediscussed further below. Provided that the hardness and rigidityrequirements for the piston as a whole are met, the rubber utilized toform the piston, and any external coating on the rubber (which may actto increase the effective hardness of the rubber), are selected forcompatibility with the medicament contained in the syringe, a number ofapproved materials being available and well known in the pharmaceuticalart.

The neck closure 60 may be formed of similar rubber, and is similar inconstruction to that shown in FIGS. 9 and 10 if lyophilization of thesyringe contents is required: otherwise the slot 63 and bores 62 (seeFIG. 9) may be omitted. After insertion of the closure 60, its flange 64may be held in place by a conventional cap 4 crimped over the flange anda flange on the neck of the bottle. Such a cap 4 may have a flip-off topattached to a separable central portion of the cap, partially severedfrom the remainder of the cap so that these portions may be broken awayprior to assembly of the syringe to expose a central needle penetrablezone of the closure 60 above the bore 61.

The piston together with its extension 18 is relatively massive, with aweight which typically amounts to at least a major portion of that ofthe body 6. This weight in the lower part of the body assists instabilising the vial during handling and filling and further inhibitstipping.

As mentioned above, vial assembly and filling will normally be performedin a clean room, since many pharmaceuticals will not withstand terminalsterilization procedures. The only additional step which requires to becarried out in the clean room other than is conventional in the fillingof vials is the insertion of the piston 8.

In order to convert the basic vial into a syringe system, either one oftwo different approaches can be used, similar respectively to thosedescribed with reference to FIGS. 1 to 6 and FIGS. 11 and 12 above. Onlythe differences from that corresponding to FIGS. 1 to 6 will bedescribed in detail for the present embodiment, since the differencesfrom the system of FIGS. 11 and 12 arrangement will in general besimilar. FIGS. 13 and 14 show the components of a syringe systemseparated, whilst FIG. 15 shown them assembled and sectioned (althoughan alternative needle arrangement is shown in FIG. 15). It should beunderstood that the diluent cartridge 14 and cartridge cap 12 areoptional features of the system and will only be utilized when a diluentor solvent is required for the content of the vial which is not providedby some other means. When building a system similar to that shown inFIGS. 11 and 12, the same parts will be used, except that if thecartridge 14 and the cap 12 are used, the cap 12 will be modified in themanner illustrated in FIGS. 11 and 12. Assembly in the manner describedwith reference to FIGS. 11 and 12 has the advantages already described.

Referring to FIGS. 13 and 15, an outer cap 2 is pushed over the cap 4,and is similar to that shown in FIGS. 1, 2 and 12, except that theinternal needle 22 shown in FIGS. 1 and 2 is omitted, the syringe beingutilized with an alternative needle arrangement. In FIG. 13, aconventional double ended needle 28, is shown, the inner end of whichreplaces the needle 22.

FIG. 15 shows an arrangement in which the needle 28 may be single ended,an auxiliary hollow needle 35 being provided with a cylindrical sleeve37 at the top which replaces the outer extremity of the inner portion ofthe coupling 27. A cap 39 is provided to retain the needle 35 within thecoupling 27 until the needle 28 is fitted. When the syringe is to beused, the cap 39 is removed, and the sleeve of the needle is placed overthe sleeve 37 and pushed down so that the needle 35 can penetrate thetop of the vial and the needle 28 can be engaged with the coupling 27.

These needle arrangements are preferred for a syringe which is shippedin an essentially ready-to-use form, since the cap 2 may be pushed fullyonto the cap 4 during assembly, yet the closure 60 remains unpenetrateduntil the needle (or other instrumentality as discussed below) is fittedat the time of use. On the other hand, the integral needle 22 isconvenient where the assembly is to be utilized in the manner shown inFIGS. 11 and 12 and a capsule 12 is utilized. The inner surface of thecap 2 is provided with longitudinal ribs 23 which indent the softaluminum of which the cap 4 is typically fabricated, and help retain thecap 2. The portions 41 and 43 of the cap 4, if present, are of coursebroken away prior to application of the cap 2.

The cap 4, closure 60, vial body 6 and piston 8 have already beendescribed in detail above. The plunger 10 differs from that shown inFIGS. 1 and 2 in two respects. Its internal threads 20 end abruptly atabutments short of the front end of the plunger, so that when theplunger is screwed onto the extension of the piston, the abutments atthe ends of the threads meet abutments at the ends of the externalgrooves on the extension which grooves in this embodiment stop short ofthe inner end of the extension, just before the inner end of the plungercontacts the rear surface of the piston. This prevents the plunger beingscrewed excessively tightly against the back of the piston in a mannerwhich might result in rocking movements of the plunger being transmitteddirectly to the piston. Instead such movements are largely absorbed bythe flexibility of the extension 18. Secondly, the flange 26 at the rearend of the plunger is moulded so that about one half of its periphery isseparated into an integral loop 11, which can be flexed rearwardly abouthinge lines 13, and serves either as a thumb loop to assist manipulationof the syringe, or a suspension loop from which the syringe can be hungduring infusion of its contents as discussed further below. Thesynthetic plastic material from which the plunger is moulded is selectedfrom those having hinge forming capability such as many pharmaceuticallyacceptable grades of polypropylene.

In order to provide further stabilization of the plunger, to prevent itswithdrawal from the body, and to provide a finger grip duringmanipulation of the syringe, particularly where longer vial bodies 6 areutilized, an optional plunger stabilizer and adapter ring 15 may beprovided. This has axially extending inner flanges 150 which enter theinner end of the body, and retaining lugs 152, which snap over the bead7. Openings 154 and flanges 156 may be provided on the rear surface ofthe ring, as required, to assist in adapting the syringe to infuserapparatus such as that shown in FIG. 8.

Where the contents of the vial are liquid and do not requirereconstitution or dilution, or reconstitution is effected by a diluentor solvent introduced via a needle or cannula through the closure 60,the cartridge cap 12 and diluent cartridge 14 are not required, thecomponents already described constituting a complete syringe system.Otherwise these components may be provided and utilized as alreadydescribed in relation to the embodiments of FIGS. 1 to 6 or FIGS. 11 and12. The components themselves are however somewhat modified as shown inFIG. 14, to facilitate handling. A skirt portion 120 of the cap isformed with longitudinal slots 122 extending from its rear edge, andinner lips 124 around the inner periphery of that edge, whilst a frontextension of the cartridge 14 is provided with ribs 142 extendinglongitudinally between the peripheral ridges 36 and 38, which ribs areaccommodated by the slots 122. The ribs 142 are continued beyond aperipheral groove behind the ridge 36. The threads 30 and the cap 12 arereduced to short ridges between certain of the slots 122. Because of theslots, the cap 12 is readily engaged over the ridge 38, but when theassembly is inserted into the interior of the plunger 10, the diameterof the cap relative to the internal chamber of the plunger 13 such thatthe lip 124 is pressed into the ring of shallow recesses defined betweenthe ridges 36 and 38 and the ribs 142, thus ensuring that the threads 30may be engaged with the threads 20 within the plunger by turning thecapsule, and inhibiting accidental forward movement of the cartridge 14into the cap 12. Further turning of the capsule drives the needle 44forward into the bore 48 (see FIG. 14) and thence through a septum inthe bore into a small diameter counterbore 46 through the head of thepiston (similar to that shown in FIG. 2), a piston modified in thismanner being utilized when a diluent cartridge is to be used. Thecartridge can then be forced forward so that the lips 124 ride over theridge 38, permitting the needle 42 to penetrate the capsule whosecontents can then be transferred to the vial by squeezing and/oraspiration.

Provided that the cap 12 is provided with a coupling 70, the capsule canof course also be utilized as described with reference to FIGS. 11 and12, in which case the passage 46 in the piston is not required.

The capsule 14 is blow moulded from a heat sealable, film grade, lowmelting, high ethylene random propylene-ethylene copolymer suitable formedical use. An example of such a material, already approved forpharmaceutical applications, is DYPRO (trade mark) polypropylene Z9350from Fina Oil and Chemical Company which has a melting point of about130° C. Such a material, formed by injection of ethylene into apropylene matrix, combines necessary qualities of transparency,impermeability and flexibility with the stability to withstandsterilizing temperatures in an autoclave, despite its low melting point;the pressure in the autoclave is maintained at a sufficient level toprevent bursting of the capsule during sterilization. Conventionalcapsule materials are unsuitable for use in this application, since theylack at least one of the necessary properties of flexibility,transparency, impermeability, penetrability, compatibility withconventional pharmaceutical diluents, and ability to withstandsterilization temperatures without failure or degradation.

Utilization of syringes incorporating the above described modificationsis similar to that of the other embodiments already described. Thecontents of the syringe may be delivered as already described withreference to FIGS. 6, 7 or 8, or in other ways. With a smallmodification to certain of the syringe components, the syringe contentsmay be reconstituted or diluted with fluid from an I.V. bag or minibag160 and then injected into the bag for delivery, as shown in FIG. 16.Both the inner and outer components of coupling adaptor 27 of the cap 2are elongated, and the bores of the inner component of the couplingadaptor and of the needle 22 are sufficient to provide an air ventingpassage around the read end of the needle 22 when fitted to the adaptor27. A locking sleeve 29 on the needle 22, which sleeve engages theadaptor 27, is provided with a ventilation opening 31, such that whenthe sleeve 29 is screwed partially onto the adaptor as shown, air canescape through the sleeve as fluid from the bag 160 enters the syringethrough the needle 22. When a desired amount of fluid has entered thesyringe, the ventilation opening is closed by screwing the needlefurther onto the adaptor, following which the contents of the syringemay be injected into the bag 160.

Referring to FIGS. 17-20 of the drawings, a syringe comprises a syringebarrel in the form of a somewhat elongated glass vial 202, of which thebottom wall is absent apart from a slight inward projection of astrengthening bead 206 formed at the bottom of a side wall 204 of thevial and best seen in FIG. 20. In the example shown the strengtheningbead 206 also has a very slight outward projection, but this is farsmaller than would be necessary if the bead were formed whollyexternally of the side wall 204, and may be entirely eliminated. In anyevent, the outward extent of the projection should be insufficient toprevent vials from standing very closely adjacent to one another withoutsufficient space to tip. Typically the projection will not exceed aboutone fifth of the total thickness of the bead. The projection of the beadon the inside should also be limited, both so that the head 210 of 1amoulded rubber piston 208 can be inserted into the vial past theprojection (this is facilitated by the presence of peripheral grooves212 in the head between sealing lands 214), and so that a sleeve 218 ofa combined finger grip, piston stop and plunger guide 216 (henceforthreferred to as the finger grip) can be pushed past the projection whilstremaining a snug fit within the side wall of the vial. Insertion isfacilitated by the slight flare provided at the bottom entry to the vialbody by the rounding of the bead, and the insertion is readilymechanized.

The piston 208 is also provided with an integrally moulded downwardextension 220 which is formed with a central cavity 223 to increase itsflexibility relative to the head 210 of the piston which issubstantially solid. The piston is dimensioned so that when it isinserted in the vial 202, the lands 214 are compressed sufficiently toform a hermetic seal against the interior of wall 204 whilst permittingthe piston to be moved longitudinally of the vial. Initially, the pistonis located at the bottom of the vial (see FIG. 18), with the bottom ofextension 220 just within the vial so that it does not affect theability of the vial to stand upright on its base formed by the bead 206.The location of the fairly massive solid rubber piston 208 at the baseof the vial helps stabilize the empty vial 202, even when the height ofthe latter is somewhat greater relative to its diameter than is normallyrequired for stability. The practical limit of the height to diameterratio is set entirely by the requirement that the vials can be conveyedthrough a conventional vial filling and capping machine in a sufficientstable manner to permit reliable operation of the machine. In theexample shown, the vial has an outside diameter of approximately 3 cmand a height of 12.8 cm for this diameter. A height of 14 centimeters isbelieved to approach the practical limit for stability, but this ratiowill vary somewhat according to the relative wall thickness of the vialand the weight of the piston. Provided that the outward projection ofthe bead 206 is insufficient to affect stability, so that the vials canjostle without applying tipping force to each other, and assuming use ofa piston generally as described, the maximum ratio attainable should begreater than 4, but will be less than 5.

The stopper 222 and cap 224 applied by the conventional vial filling andcapping machinery may be of conventional construction, although thestopper 222 is preferably designed substantially to fill the neck of thevial so as to minimize dead space above the piston when the latter ispushed to the top of the vial (see FIG. 3). This ensures that as much aspossible of the contents of a syringe formed from the vial can beexpelled by movement of the piston.

The cap 224 is preferably modified as shown in FIG. 19 and FIG. 20. InFIG. 19, a conventional main cap cooperates with a moulded plasticadaptor assembly comprising an annular flange 226 within the cap, acylindrical extension 228 extending through the cap and a thin diaphragm230 closing a bottom end of the extension. An internal thread 232,similar to that provided on conventional syringe adaptors for receivingneedles, such as those sold under the trade-mark LUER-LOK, is formedwithin the adaptor. A removable push on cap may be provided to close theopen end of the adaptor during storage, being removed prior to use. InFIG. 20, the cylindrical extension 228 is formed integrally with thealuminum cap, again with an internal thread 232. I have found that theextension 228 can be accommodated by conventional vial cappingmachinery, at any rate with no more than minor modification, withoutinterfering with the capping process, whilst the provision of such anextension enables the elimination of a separate adaptor cap, and theadditional assembly step required to apply it.

In order to convert the vial into a syringe, either a double endedneedle 234 of the blood collecting type may be applied directly to theextension 228 (see FIG. 20) or an adaptor 236 (see FIGS. 17 and 19) maybe provided for any needle or alternative delivery device equipped witha standard syringe coupling so as to provide the latter with thecapability of penetrating the stopper 222, as well as the diaphragm 230if present. The adaptor 236 has a needle 238 and external thread 240 atone end, the needle providing the penetration function and the thread240 engaging the thread 232, while its other end provides an internallythreaded socket 242 and coaxial spigot 244 for forming a fluid-tightcoupling to the needle or the like.

Prior to fitting the double ended needle 234, or needle and adaptor 236,a plunger 246 is applied to the extension 220 of the piston. The plungerhas a shaft 248, of cruciform cross-section in the example shown, aninternally threaded sleeve 250 at its one end, and an end flange 252 atits other end. The sleeve 250 has internal multistart threads 254,complementary to external multistart threads 256 on the extension 220.The lands between the threads 254 on the sleeve 250 and the threads 256on the extension 220 both stop short respectively of the outer end ofthe sleeve 250 and the inner end of the extension 220 so as to formabutments 258, 260 which prevent the sleeve 250 from being screwedtightly against the underside of the head 210 of the piston. This meansthat any tilting forces applied to the plunger are applied to therelatively flexible extension 220 and not directly to the head 210, thusminimizing the risk of breaking the hermetic seal between the head 210and the vial.

The plunger is formed of a hinge-forming synthetic plastic such as apharmaceutical grade polypropylene, and a generally semicircularperipheral portion 262 of the flange and is separated from the remainderof a slot 264, remaining connected only by thin, hinge-formingconnections 266. This portion 262 provides a finger loop which can bepulled rearwardly, as shown by broken lines in FIG. 1, to facilitatehandling of the plunger. As a supplemental or alternative feature, anotch 272 may be formed in the shaft 248 of the plunger, to provide ahook by means of which the syringe may be suspended when used in certaininfusion applications.

In order to provide the various functions of preventing total withdrawalof the piston, forming a guide for the plunger and restricting itstilting movements, and providing a finger grip for the user, thecombined finger grip and retainer 216 is pressed into the bottom of thevial 202 after filling and capping of the latter. It comprises thesleeve 218 and a peripheral flange forming oppositely extending fingergrips 268. It is also moulded from a pharmaceutical grade of plasticsuch as polypropylene. The sleeve 218 is a resilient press fit in theopen end of the vial 204 so that it is slightly compressed by theinternal projection of the bead 206 during insertion. Insertion of theretainer 216 may be facilitated by moderate warming of at least theretainer, and the slight flare provided by the rounding of the bead 206also facilitates insertion. Beneath the grips 268 the sleeve has shallowarcuate grooves 270 in which the bead 206 snaps as the sleeve is pressedhome. Forces applied to the grips 268 tending to pull the sleeve 218away from the vial in turn tend to deform the sleeve, in such a manneras to increase the grip of the grooves 2700 on the bead thus resistingwithdrawal of the sleeve.

During manufacture, the empty vials 204 are conveyed through aconventional sterilizing station, the piston 208 is inserted in eachvial 204, and the latter is filled and capped utilizing conventionalvial filling and capping machinery (but preferably using a modified capas shown in FIGS. 17 and 19 or FIG. 20). The guide and finger grip 218is then pressed into the base of the vial, which is shipped with theplunger 246 unattached. Prior to use, the plunger 246 is screwed ontothe piston, and a needle or the like is applied to the extension 228,utilizing an adaptor 236 if necessary so as to penetrate the stopper222, at which point the syringe is ready for use.

A modified configuration of the bottom end of the vial body is shown inFIG. 21, in which an alternative approach is utilized to bringing thebead at the bottom end substantially within the diameter of thecylindrical vial body. Peripheral beads around the openings of glassbodies of this type are conventionally formed by flame softening theglass and adjusting the positioning and profile of the bead by rollingthe body against suitable forming surfaces. In the FIG. 5 embodiment, abottom portion 274 of the body 204 is flame softened and rolled so asslightly to reduce its diameter over about a length of typically 5-6 mm,and a fairly conventional out-turned rounded bead 206 is formed byflaring the bottom of this reduced diameter section. The reduction indiameter is such that at least the greater part of the bead is withinthe general diameter of the body. In the example shown, the outsidediameter of the bead is very slightly greater than the general outsidediameter of the body but this need not be so. In a typical example, theinside and outside diameters of the main portion of the vial body are 27mm and 30 mm respectively, providing a wall thickness of 1.5 mm, and thereduction in diameter at the bottom is about 1 mm. The bead can then beformed by flaring the bottom end of the vial without increasing theoutside diameter of the bead significantly beyond that of the mainportion of the vial and typically by no more than 0.5 mm, even though asignificant flare 276 can be provided and, because of the flare, thebottom contact line 278 of the vial when free-standing on a planesurface is substantially coincident with the outside diameter of themain body 204 of the vial, thus maximizing stability. Juxtaposition ofthe vial bodies in the event of jostling on a line will prevent anyramping tendencies which might otherwise occur with a flared bottomconfiguration of this type.

Whilst the presence of the piston after its insertion in the vial bodyacts to introduce a substantial mass which trends to stabilize the vial,the mass of the piston relative to that of the vial body will decreaseas the height of the latter increases. Nevertheless it will result in asmaller rise of the centre of gravity of the assembly as the vialbecomes higher than would otherwise be the case. It is also desirablethat the vial bodies be stable without the piston present so that theymay be conveyed through a stabilizer prior to insertion of the pistons.The present invention is particularly valuable in this respect since thedisturbing influence of a bead at the open end projecting beyond thediameter of the main portion of the body is particularly severe undersuch conditions.

In order to cooperate with the modified vial body profile, the fingergrip/retainer 216 must also be modified. The groove 270 is replaced by abead 280 at the upper end of the cylindrical portion 218, which bead maybe moulded with a taper and if necessary with slots 282 to facilitateinsertion, and/or the component 16 may be warmed to facilitateinsertion. The bead must retain the component with sufficient tenacityto withstand pressures from the piston which may be developed throughpressure build-up in the vial during normal storage, although it shouldbe noted that pressure of the piston on the bead may actually helpretain it by forcing it against the shoulder 284. Alternatively oradditionally, claws 286 may be moulded onto the component 216 to retainit by external engagement with the bead 206.

Referring now to FIGS. 22 and 23, shell vials are a well known andwidely available packaging for pharmaceutical diluents. A shall vialdiffers from a conventional pharmaceutical or serum vial in that it hasno neck. Instead the top of the vial is of the same diameter as theremainder of the cylindrical side wall of the vial, and is closed by apiston quite similar to that utilized by the present applicant to closethe bottom of his bottomless vial.

FIG. 22A shows an exploded view of the components of a separatelyassembled and sterilized unit 300 for use in conjunction with a filledand capped vial 302 similar to that shown at the right of FIG. 12. Theunit 300 comprises a shell vial having a cylindrical body 304 closed atone end, and a piston 306 closing its other end to enclose a quantity ofpharmaceutical diluent. A moulded plastic tubular adaptor component 308having a tubular connector 310 at one end similar to the connectorelement 700 of FIG. 12, and an internal thread 312 within its other endis engaged with an external thread on a extension 314 of the piston 306.The unit further includes a tubular plunger 316 similar to the plunger10 of FIG. 12, a cap 318 similar to the cap 2 of FIG. 12, a needle 320,and a protective cap 322 which closes the open end of the cap tomaintain sterility and provide protection of the needle during storage.This cap is removed immediately before use (see FIG. 22C). The needle320 is of the double ended type, and is located beneath the cap 318 by aflange 324. A connector 326 on the cap similar to the connector 27 ofFIG. 12 engages the connector 310 on the adaptor component 308 in thesame way as the connector 27 engages the connector 70 in FIG. 12, sothat one end of the needle 320 passes through the adaptor towards thepiston extension 314, as seen in FIG. 22B.

After the cap 22 has been removed (FIG. 22C), and also a flip-offprotective cover 328 on the cap of the vial 302 (FIG. 22D), the unit 300is pressed on the vial 302 (FIG. 22E) so that the cap 318 is pressedover the cap 330 of the vial 302 so that the lower end of the needle 320pierces the closure of the vial 302. At the same time, the flange 324 ispressed upwardly within the cap 318 and causes the upper end of theneedle 320 to penetrate a septum within the piston 306.

The shell vial 304 is then pressed downwardly (FIG. 22F) expelling itscontents through the needle 320 into the vial 302. If necessary, thepiston 332 within the vial 302 is positioned higher in the vial thannormal so that it can be displaced downwardly to make room for thecontents of vial 304 (see FIG. 22G).

At this point, the assembly 300, with the exception of the cap 318 andthe needle 320, is pulled away from the vial 302 by gripping the plunger316 leaving the cap and needle in place on the vial (FIG. 22G). Theplunger 316 is then screwed onto the piston 332 of the vial 302 (FIG.22H) to form a syringe 334 (FIG. 22I).

In the embodiment just described, the shell vial is dimensioned so as tofit within the tubular plunger. An alternative embodiment is shown inFIGS. 23A-G in which the shell vial 304 is dimensioned so that thetubular plunger 316 has an external diameter less than its internaldiameter. The same reference numerals are used to denote components ofthis embodiment similar to those of FIG. 22A-I, and only the differenceswill be described. In this instance, the plunger 316 fulfils thefunctions of the adaptor 308, the screw threads on the pistons 306 and332 being similar except that the thread 314 on piston 306 may belonger. The plunger 316 is a press fit on the connector 326 on the cap318, which in this case is formed with a skirt 336 which fits over thetop portion of the vial 302 and also provides a finger grip 338. Theentire unit 300 (see FIG. 23C) is assembled into a tubular sleeve 340(FIG. 23B) which together with the cap 322 maintains sterility of theunit during storage, and also facilitates preparation of the syringe.The vial 304 is a press fit within the upper end of the sleeve 340.After removal of the cap 322, the unit 300 is applied to the vial (FIG.23D) as in the previous embodiment, and the sleeve 340 is pulleddownwardly (FIG. 23E). As before, this forces the cap 318 onto the cap330 of the vial, causing the needle 320 to pierce both the closure ofthe vial 302 and the piston 306 of the shell vial 304, and furtherdownward movement of the sleeve 340 forces the contents of the shellvial into the vial 302. At this point the sleeve 340 is rotated tounscrew the piston 306 of the shell vial 304 from the plunger 316 (FIG.23F) which is then transformed to the piston 332 to complete thesyringe.

It should be understood that the sleeve 340 could be omitted, althoughit is a convenience for packaging and manipulating the syringe, in whichcase the vial 304 would be manipulated directly rather than through thesleeve 340.

Variations in the above embodiments are possible. For some applicationsof the syringe, it may be desired to replace the needle 320 by someother instrumentality when the syringe is used, in which case a singleended needle may be located in the assembly 300 so that it will beforced upwardly as the cap 318 is forced onto the vial 302 (the cap inthis case will have an internal cannula to piece the closure of thevial), but will be retained within the shell vial when the latter isremoved during preparation of the syringe. If a double ended needle 30is used, in combination with a cannula, venting of the vial 302 topermit escape of sir displaced by the contents of the shell vial 304becomes possible, in a manner similar to that shown in FIG. 16.

A sleeve similar to the sleeve 340 may also have utility in packagingand manipulating subassemblies for other embodiments of the inventionincorporating push-on external caps for the vial similar to the cap 318.

I claim:
 1. In a method of packaging a pharmaceutical in apharmaceutical vial formed of rigid transparent material with acylindrical body and a comparatively wide open neck at the top of thebody, which method comprises conveying uncapped vials, empty ofpharmaceutical, in a free-standing upright position through vial fillingand capping machinery which fills the pharmaceutical into the bodythrough the open neck, applies an elastomeric closure to the open neck,and applies a cap overlaying the closure to secure the closure to theneck to produce filled and capped vials, the improvement in which, inorder to permit subsequent administration via injection direct from thevial, a cylindrical side wall of each uncapped empty vial is formed soas to define a bottom opening at the base of the vial with a beadadjacent to the bottom opening, the outer wall of the vial being free ofany external projection of the bead relative thereto sufficient to causesubstantial instability of the vial when conveyed upright andfree-standing adjacent to other similar vials during filling andcapping, and a cylindrical substantially solid piston of resilientmaterial is slidably lodged prior to filling of the vial wholely withinthe cylindrical side wall above said bottom opening so as to form ahermetic seal with the side wall, so that an internal and axialextension from the piston, of lesser diameter than the piston andadapted for subsequent coupling to a syringe plunger, is oriented so asto extend downwardly within the vial towards the bottom opening.
 2. Amethod according to claim 1, including the further step, followingfilling and capping, of snap fitting a piston stabilizer ring to thebead so that flanges on the piston stabilizer ring extend into the bodybetween the cylindrical side wall and the piston extension to preventescape of the piston from the body.